Preparation of pharmaceutical salts

ABSTRACT

In one embodiment, the present invention discloses a process to directly prepare an unequal ratio of rotamers of an acid salt from a basic compound, by creative choice of a solvent medium. The process is particularly useful in preparing specific rotamers of pharmaceutically useful salts in desired preponderance.

FIELD OF THE INVENTION

[0001] This patent application generally discloses a novel process toprepare pharmaceutically useful salts. It specifically discloses a novelprocess to synthesize pharmaceutically useful salts of piperidine,4-[4-[(1R)-[4-(trifluoromethyl)phenyl]-2-methoxyethyl]-(3S)-methyl-1-piperazinyl]-4-methyl-1-[(4,6-dimethyl-5-pyrimidinyl)carbonyl].It further discloses a process to prepare pharmaceutical salts that areenriched in desired specific rotameric configurations. This applicationclaims priority from U.S. provisional patent application, Docket No.60/334,331 filed Nov. 29, 2001 and U.S. provisional patent application,Docket No. 60/373,916 filed Apr. 19, 2002.

BACKGROUND OF THE INVENTION

[0002] Piperidine,4-[4-[(1R)-[4-(trifluoromethyl)phenyl]-2-methoxyethyl]-(3S)-methyl-1-piperazinyl]-4-methyl-1-[(4,6-dimethyl-5-pyrimidinyl)carbonyl](Formula I) is disclosed in pending U.S. patent application, Ser. No.09/562,814 filed on May 1, 2000, incorporated herein by reference.

[0003] That U.S. patent application, Ser. No. 09/562,814, disclosesseveral novel antagonists of the CCR5 receptor which are useful for thetreatment of AIDS and related HIV infections, including the compound ofFormula I. CCR-5 receptors have also been reported to mediate celltransfer in inflammatory diseases such as arthritis, rheumatoidarthritis, atopic dermatitis, psoriasis, asthma and allergies, andinhibitors of such receptors are expected to be useful in the treatmentof such diseases, and in the treatment of other inflammatory diseases orconditions such as inflammatory bowel disease, multiple sclerosis, solidorgan transplant rejection and graft v. host disease.

[0004] Generally, pharmaceutical compounds are used as theirpharmaceutically acceptable salts. This is true of CCR5 receptorantagonists such as the compound of Formula I too, which makes thepreparation of pharmaceutically acceptable salts of such compounds quiteimportant.

[0005] The compound of Formula I has two chiral centers and the absoluteconfigurations of the chiral centers are controlled by the chemicalsynthesis. However, the compound of Formula I exists as a mixture ofrotational isomers or rotamers. There are two rotamers(diastereoisomers) resulting from restricted rotation about the amidebond marked in the figure in Scheme 1. The two rotamers may be denotedas isomers 1 and 2, in order of their elution from a HPLC column (Scheme1):

[0006] While general synthetic approaches for salts typically yield a1:1 ratio of the rotamers 1 and 2, it would be preferable to findmethods of synthesis that would yield rotamer populations that areenriched in certain rotamers preferentially.

SUMMARY OF THE INVENTION

[0007] In an embodiment, the present invention discloses a uniqueprocess for preparing a mixture of rotamers of a salt of a basiccompound wherein said mixture comprises one or more rotamers of saidsalt in a higher (i.e., preferentially enriched) molar percent thantheir corresponding rotamers of said salt, with the process comprisingreacting said basic compound with an acid in admixture with a solvent.It also teaches a method for preparing pharmaceutically useful salts. Itspecifically teaches a method for the formation of the salts,pharmaceutically useful or otherwise, of the compound of Formula I inhigh yields. It also teaches the direct, enriched preparation ofspecific, preferential rotamers of a salt of the compound of Formula Iin high yields and in higher molar percent than other correspondingrotamers of the salt.

[0008] The term “high yields” refers to at least about 50% yield of thedesired enriched product. Thus, unlike previously known processes whichresult in a 1:1 ratio of the salts of the rotamers 1 and 2, the presentprocess offers a way to obtain the selective formation of unequal ratiosof the salts of the desired rotamer directly. The term “higher molarpercent” refers to selective preferred formation of a certain rotamer(or diastereoisomer ) or rotamers over the other corresponding rotamer(or diastereoisomer) or rotamers by at least about a 55:45 ratio ofmolar percent. The formation of such differential ratio of rotamer (ordiastereoisomer) directly in the present process is influenced by theunique choice of the solvent medium for the reaction between theparticular acid and the basic compound. The term ‘directly’ means‘without the need for an additional step to separate the 50:50 rotamersobtained, for example, in the conventional process’. Thus, for example,if rotamer 2 is the desired one with high pharmaceutical activity, thepresent process makes it possible to obtain that rotamer directlyinstead of having to make an equimolar mixture of the rotamers 1 and 2by previously known processes, followed by cumbersome separation of themixture; such a separation may or may not yield the desired salt indecent yields and the process is also likely to be expensive.

[0009] Since the activity of pharmaceutical compositions may differdepending upon the type of salt they are comprised of, the presentprocess affords a unique way to obtain desired specific salts with goodpharmaceutical activity in highly enriched rotameric content. In thecase of the compound of Formula I, the present process achieves suchpreferential formation of the isomers by creative selection of the acid(for salt formation) and solvent medium for the salt-forming reaction.

[0010] The inventive process to make differing ratio of the rotamers ofthe salts of the compound of Formula I has several advantages: it iseconomical, can be easily scaled-up, affords the desired, preferentiallyenriched rotamer ratio in high yields and is generically applicable.

DESCRIPTION OF THE INVENTION

[0011] In one embodiment, the present invention discloses a novel,easy-to-use process for preparing a pharmaceutical salt of a basiccompound in high yields. In another embodiment, the present inventiondiscloses a novel, easy-to-use process for preparing a pharmaceuticalsalt of a basic compound of Formula I in high yields. It also teachesthe preferential preparation of specific rotamers of the salt of thecompound of Formula I in high yields. In another embodiment, the presentprocess, while described and illustrated herein as the preparation ofspecific desired rotamers of the compound of Formula I, is simple enoughto be applicable generically to the preparation of pharmaceuticallyuseful salts from a basic pharmaceutical composition. The presentprocess comprises reacting the compound of Formula I (or a similar base)with an acid in admixture with a selected solvent medium in order toobtain differing ratios of rotamers as salts. The term “admixture”refers to physical contact of the ingredients as is known to thoseskilled in the art such as, for example, solution, suspension, emulsion,contact through a matrix such as, running through a column, and thelike.

[0012] Thus, in another embodiment, the invention offers a novel, simpleprocess to directly prepare desired salts of a basic compound in anunequal ratio of rotameric populations. In yet another embodiment, thepresent invention teaches the formation of pharmaceutically useful saltsin high yields and selectivity of rotamer population.

[0013] In an illustrative embodiment, the present process offers a wayto directly obtain at least about 55 mole percent of rotamer 2 and about45 mole percent of rotamer 1 in the salt of the compound of Formula I.In many instances, it affords a way to obtain rotamer 2 and rotamer 1 ina molar percent ratio of 75:25 respectively. In fact, in severalinstances, it affords rotamer 2 in even greater than 90 molar percent.Specifically, the present process achieves such preferential formationof the desired rotamer of the salt of the compound of Formula I bycreative selection of the acid (for salt formation) and solvent mediumfor the salt-forming reaction.

[0014] The process, while described and illustrated herein as thepreparation of specific desired rotamers of the compound of Formula I,is simple enough to be applicable generically to the preparation ofpharmaceutically useful salts from basic pharmaceutical compositions. Byappropriate choice of the solvent medium, the reaction of the basiccompound with an acid (from which the salt is to be derived) to form thesalt selectively yields the desired rotameric compositions in enrichedmolar percent. Thus, in another embodiment, the invention offers anovel, simple process to directly prepare desired salts of basiccompounds in an unequal ratio of rotamers. In yet another embodiment,the present invention teaches the formation of pharmaceutically usefulsalts in high yields and selectivity of rotamer population.

[0015] The following non-limiting list includes anions representingsuitable acids which may be used to form salts in accordance with thepresent invention. The list of anions for useful salts includes, forexample, acetate, benzenesulfonate, benzoate, bicarbonate, bromide,calcium edetate, camphorsulfonate, carbonate, chloride/dihydrochloride,citrate, N,N-di(dehydroabietyl)ethylenediamine, edetate,1,2-ethanedisulfonate, ethanesulfonate, fumarate, glucoheptonate,gluconate, glutamate, p-glycollamidophenylarsonate, hexylresorcinate,hyclate, hydrobromide, hydrochloride, 2-hydroxyethanesulfonate,hydroxynaphthoate, iodide, lactate, lactobionate, lauryl sulfonate,malate, maleate, mandelate, methanesulfonate, methylbromide,methyinitrate, methylsulfate, mucate, nafate, napsylate, nitrate,pamoate, pantothenate, phosphate/diphosphate, polygalacturonate,salicyclate, sodium succinate, stearate, subacetate, succinate, sulfate,tosylate, tannate, tartarate/bitartarate, 8-chlorotheophyllinate,triethiodide, adipate, alginate, aminosalicyclate,anhydromethylenecitrate, arecoline, asparate, bisulfate, butylbromide,camphorate, digluconate, dihydrobromide, disuccinate, glycerophosphate,hemisulfate, hydrofluoride, hydroiodide, methylenebis(salicyclate),naphthalenedisulfonate, oxalate, pectinate, persulfate,phenylethylbarbiturate, picrate, propionate, thiocyanate, undecanoate,acetylaminoacetate, N-acetyl-L-asparaginate, N-acetylcystinate,adamantoate, adipoate, N-alkylsulfamates, anthraquinone-1,5-disulfonate,arabolactansulfate, argininate, aspartate, betaine, carnitine,4-chloro-m-toluenesulfonate, decanoate, diacetyl sulfate,dibenzylethylenediamine, dimethylamine, diguaiacylphosphate,dioctylsulfosuccinate, pamoate, fructose-1,6-diphosphate, glucosephosphate, L-glutaminate, hydroxynaphthoate, lauryl sulfate, lysine,2-naphthenesulfonate, octanonate, tannate and theobromine acetate.Additionally, acids which are generally considered suitable for theformation of pharmaceutically useful salts from basic pharmaceuticalcompounds are discussed, for example, by S. Berge et al, Journal ofPharmaceutical Sciences (1977)66(1 ), 1-19; P. Gould, International J.of Pharmaceutics (1986) 33 201-217; Anderson et al, “The Practice ofMedicinal Chemistry” (1996), Academic Press, New York; and in The OrangeBook (Food & Drug Administration, Washington, D.C. on their website).These disclosures are incorporated herein by reference. Mono- and di-salts are included.

[0016] Generally, known processes to form salts by reaction of basiccompounds with acids yield equal ratios of rotamers which need to belater separated in yet another step. The present process, which avoidssuch separation by preferentially enriching in certain rotamerpopulations during the salt formation reaction itself is superior.

[0017] The present process may be illustrated by the formation of themaleate salt of the compound of Formula I. The compound of Formula I,which is basic, may be dissolved in a suitable solvent. Suitablesolvents include alcohol, ester, ketone, hydrocarbon or mixturesthereof. Non-limiting examples of such suitable solvents are ethylacetate, isopropyl acetate, isopropyl alcohol, ethyl alcohol, acetone,hexane, toluene, heptane and the like, and mixtures thereof. Preferredsolvents are ethyl acetate or isopropyl acetate. Maleic acid may beadded to this either as a solid or as a solution in the same solvent.The acid is used generally in a 5:1 mole ratio, preferably in a 2:1molar ratio and typically in a 1:1 molar ratio, with respect to thecompound of Formula I. The total quantity of the solvent may generallybe in about a 20:1 ratio, preferably about a 10:1 ratio and typicallyabout a 6:1 ratio, with respect to the compound of Formula I. Themixture is stirred or intimately mixed otherwise, generally at about25-90° C., preferably at about 50-90° C. and typically at about 60-80°C. for a duration of about 1-48 hours generally, about 1-36 hourspreferably, and about 1-24 hours typically, and then kept at about theambient conditions to allow the completion of salt formation, usually ascrystals. Seeding may be done if necessary or desired. The salt may beisolated by filtration or such similar methods. The rotameric ratio maybe determined by methods known to those skilled in the art such as, forexample, HPLC, HMR and the like, as is well known to those skilled inthe art. In an illustrative experiment involving the compound of FormulaI, when ethyl acetate or isopropyl acetate was used as the solvent andmaleic acid as the acid, a diastereomeric ratio of >2:98 (for the isomer1 to the isomer 2) was found in the maleate salt formed from thereaction. Similar results were obtained for salts prepared with acidsother than maleic acid too.

[0018] The salts prepared by the present invention exhibit desirablephysical and chemical characteristics suitable for pharmaceutical uses.Non-limiting examples of such characteristics include physicalstability, chemical stability, thermal stability, desirablehygroscopicity, solubility, fluidity and the like.

[0019] The following nonlimiting EXAMPLES and TABLE 1 are provided inorder to further illustrate the present invention.

EXAMPLES

[0020] Unless otherwise stated, the following abbreviations have thestated meanings in the Examples and Table 1 below:

[0021] HPLC=High Performance Liquid Chromatography

[0022] M.pt: melting point

[0023] NMR=nuclear magnetic resonance spectroscopy

[0024] mL=milliliters

[0025] mmol=millimoles

[0026] g=grams

[0027] rt=room temperature (ambient)

[0028] THF=Tetrahydrofuran

[0029] TBME=Methyl t-butyl ether

[0030] ACN=Acetonitrile

[0031] EtOH=Ethanol

[0032] EtOAc=Ethyl acetate

[0033] iPrOAc=Isopropyl acetate

EXAMPLES Example 1

[0034] Mono-Benzenesulfonic Acid Salt of the Compound of Formula I:

[0035] To 0.2 g (0.37 mmol) of the amine compound of Formula I dissolvedin 1 mL ethyl acetate at 40° C. was added a solution of 0.06 g (0.38mmol) benzene sulfonic acid in 1.5 mL EtOAc at 40° C. The solution wasstirred 2 days and filtered. Solids were washed with 0.5 mL ethylacetate and dried to give 40 mg of the mono-benzene sulfonate salt with8.7:91.3 ratio of rotamers 1 to 2.

Example 2

[0036] Di-benzenesulfonic Acid Salt of the Compound of Formula I:

[0037] To 0.3 g ((0.55 mmol) of the amine compound of Formula Idissolved in 1 mL ethyl acetate at 40° C. was added a solution of 0.18 g(1.12 mmol) benzene sulfonic acid in 3 mL ethyl acetate at 40° C. Thesolution was stirred 2 days and filtered. Solids were washed with 0.5 mLethyl acetate and dried to give 0.26 g of di-benzene sulfonate salt in51.3% yield.

Example 3

[0038] Citric Acid salt of the Compound of Formula I:

[0039] To 6.14 g (9.18 mmol) of the amine compound of Formula Idissolved in 15 mL of acetone at 23° C. was added 1.77 g (9.17 mmol) ofsolid citric acid. The mixture was heated to 50° C. and allowed to coolto room temperature. The mixture was stirred for 23 hr and 15 mL ofacetone was added. The solids were filtered, washed with 15 mL ofacetone and dried to give 5.05 g of the citrate salt in 76% yield with1:99 ratio of rotamers 1 to 2.

Example 4

[0040] Mono-hydrochloric Acid Salt of the Compound of Formula I:

[0041] To 0.28 g (0.525 mmol) of the amine compound of Formula Idissolved in 1 mL MTBE at 23° C. was added 0.043 mL (0.52 mmol) 12 M HClsolution. The mixture was stirred for 10 days as the product slowlysolidified. Two mL of TBME was added, the solids were filtered, washedwith 2 mL THF and dried to give 0.25 g of the mono HCl salt in 85%yield.

Example 5

[0042] Di-hydrochloric Acid Salt of the Compound of Formula I:

[0043] To 5.02 g (9.22 mmol) of the amine compound of Formula Idissolved in 22.5 mL of 2:1 THF: toluene at 23° C. was added 1.55 ml(18.7 mmol) 12 M HCl solution. The mixture was stirred for 23 hr andfiltered. The solids were washed with 15 mL THF and dried to give 5.2 gof the di-HCl salt in 92% yield with 1:99 ratio of rotamers 1 to 2.

Example 6

[0044] Fumaric Acid Salt of the Compound of Formula I:

[0045] To 0.5 g (0.92 mmol) of the amine compound of Formula I dissolvedin 0.5 mL toluene and 2.5 mL acetone at room temperature was added0.1145 g (0.987 mmol) fumaric acid and 2.5 mL acetone. The solution wasstirred for 2 days, cooled to 0° C. and filtered to give 0.29 g of themono-fumarate salt.

Example 7

[0046] Di-phosphoric Acid Salt of the Compound of Formula I:

[0047] To 0.30 g (0.55 mmol) of the amine compound of Formula Idissolved in 1.5 mL isopropyl alcohol was added 75 μL (1.10 mmol) 85%phosphoric acid at 40° C. The solution was stirred for 2 days, filteredand dried to give 0.35 g of the diphosphate salt in 85.2% yield.

Example 8

[0048] Mono-p-toluene Sulfonic Acid Salt of the Compound of Formula I:

[0049] To 0.23 g (0.44 mmol) of the amine compound of Formula Idissolved in 1 mL isopropyl acetate at 40° C. was added a solution of0.0845 g (0.24 mmol) p-toluene sulfonic acid monohydrate in 1.5 mLisopropyl acetate at 40° C. The solution was stirred 2 days andfiltered. Solids were washed with 0.5 mL isopropyl acetate and dried togive 0.17 g of mono-PTSA salt in 54.6% yield with 7.7:92.3 ratio ofrotamers 1 to 2.

Example 9

[0050] Di-p-toluene Sulfonic Acid Salt of the Compound of Formula I:

[0051] To 0.30 g (0.44 mmol) of the amine compound of Formula Idissolved in 1 mL acetone at 40° C. was added a solution of 0.1686 g(0.89 mmol) p-toluene sulfonic acid monohydrate in 3 mL acetone at 40°C. The solution was stirred 2 days and filtered. Solids were washed with1.5 mL acetone and dried to give 0.2 g of the di-PTSA salt.

[0052] The following Examples illustrate the preparation of the maleicacid salt of the compound of Formula I from different solvents:

Example 10a

[0053] From Isopropanol:

[0054] The amine compound of Formula I (3.0 g, 93.6% pure) and maleicacid (0.65 g) were mixed and dissolved in isopropanol (12 mL). Themixture was stirred at room temperature for about 1 h resulting in acloudy solution. Crystalline seeds were added and the resulting slurrywas stirred at room temperature for about 21 h. The product was filteredand dried overnight at 55° C. under vacuum to give a white solid (3.0 g,88% yield). Ratio of rotamers 1 to 2: 1.1:98.9.

Example 10b

[0055] From Ethanol/Toluene mixture:

[0056] The amine compound of Formula I (10 g) in ethyl acetate (about 35mL) was mixed with a solution of maleic acid (2.17 g) in methanol (10mL) at room temperature. The mixture was concentrated under vacuum andthe residue was redissolved in ethanol (10 mL). Toluene (125 mL) wasadded slowly at 60° C. to give a milky solution. The mixture was cooledto room temperature over 2 h and seeded. The mixture was stirred at roomtemperature for about 2.5 days. The product was filtered and dried for18 h at 45° C. under vacuum to give a white solid (8.66 g, 71% yield).Ratio of rotamers 1 to 2: 1.8:98.2.

Example 10c

[0057] From Ethanol/Ethyl Acetate Mixture:

[0058] The amine compound of Formula I (10 g) in ethyl acetate (35 mL)was mixed with a solution of maleic acid (2.18 g) in ethanol (10 mL) atroom temperature. Crystalline seeds were added and the mixture wasstirred at room temperature for 22 h. The slurry was cooled gradually to−10° C. and stirred at that temperature for 4 h. The product wasfiltered, washed with ethyl acetate (10 mL), and dried overnight at 64°C. under vacuum to give the desired salt as a white solid. Ratio ofrotamer 1 to 2: 2.3:97.7.

Example 10d

[0059] From Isopropanol/Ethyl Acetate:

[0060] The amine compound of Formula I (10 g) in ethyl acetate (40 mL)was mixed with a solution of maleic acid (2.2 g) in isopropanol (20 mL)at 55° C. The cloudy mixture was seeded, cooled slowly to 40° C., andstirred at 40° C. overnight. The resulting slurry was cooled graduallyto room temperature and stirred overnight. The product was filtered,washed with 2:1 ethyl acetate/isopropanol (30 mL), and dried overnightat 55° C. under vacuum to give the desired salt as a white solid. Ratioof rotamers 1 to 2: 0.9:99.1.

Example 10e

[0061] From Ethyl Acetate:

[0062] The amine compound of Formula I (26 g) in ethyl acetate (26 mL)was mixed with a solution of maleic acid (5.7 g) in Ethyl Acetate (74mL) at 60° C. The solution was seeded at 60° C. and stirred at 60° C.overnight. The resulting slurry was cooled gradually to room temperatureand to 0° C. for 2 hours. The product was filtered, and dried overnightat 25° C. under vacuum to give a white solid (27.6 g, 87% yield). Ratioof rotamers 1 to 2: 1.8:98.2.

Example 10f

[0063] From Ethyl Acetate/Heptane:

[0064] The amine compound of Formula I (20 g) in ethyl acetate (20 mL)was mixed with a solution of maleic acid (4.4 g) in Ethyl Acetate (60mL) at 65° C. The solution was seeded at 65° C. and stirred at 65° C.for 1 hours. Then 20 mL of Heptane was added to the slurry at 65° C.After stirring at 65° C. overnight, the slurry was cooled gradually toroom temperature and to 0° C. for 2 hours. The product was filtered, anddried overnight at 25° C. under vacuum to give a white solid (22.3 g,92% yield). Ratio of rotamers 1 to 2: 1.9:98.1.

Example 10g

[0065] From Isopropyl Acetate:

[0066] Maleic acid (4.4 g) was dissolved in 100 mL of Isopropyl acetateat 75° C. The solution of the amine compound of Formula I (20 g) inIsopropyl acetate (20 mL) was added to the maleic acid solution at 75°C. After stirring at 75° C. overnight, the resulting slurry was cooledgradually to room temperature and to 0° C. for 2 hours. The product wasfiltered, and dried overnight at 25° C. under vacuum to give a whitesolid (22.1 g, 91% yield). M.pt. 183.5° C. Ratio of rotamers 1 to 2:1.8:98.2. TABLE 1 Solvent (diastereomeric ratio 1 to 2 in solids) SaltYield %  1. Mono- Ethyl Acetate Benzene (8.7:91.3) sulfonate  2.Di-Benzene Ethyl Acetate TBME sulfonate 51% yield 94% yield  3.(1S)-(+)- THF/TBME Camphorsulf- (50:50) onate  4. Citrate Acetone (1:99) 5. Mono- TBME hydrochloride 85% yield  6. Di-hydrochloride THE/Toluene(1:99)  7. Fumarate Acetone Acetonitrile iPrOAc Acetone/ 66% yield 76%yield 51% yield Toluene  8. Di-Phosphate Acetone Ethyl Acetate Isopropyl69% yield 57% yield alcohol 85% yield  9. Mono-Tosylate Ethyl AcetateiPrOAc (7.7:92.3) 10 Di-Tosylate Acetone Ethyl Acetate IPrOAc IsopropylTBME 50% yield or alcohol 99.5% Toluene yield 11 Maleate Ethyl AcetateiPrOAc EtOH/Ethyl Isopropyl (1.8:98.2) (1.8:98.2) Acetate alcohol EthylAcetate/ (2.3:97.7) (1.1:98.9) Heptane EtOH/ Isopropyl (1.9:98.1)toluene alcohol/ (1.8:98.2) EtOAc (0.9:99.1)

[0067] While the EXAMPLES and TABLE 1 are described herein as thepreparation of the diastereomeric isomer of the salts of the compound ofFormula I, it will be apparent to those skilled in the art that manymodifications, variations and alterations to the present disclosure,both to materials, methods and reaction conditions, may be practiced.All such modifications, variations and alterations are intended to bewithin the spirit and scope of the present invention.

What is claimed is:
 1. A process for preparing a mixture of rotamers ofa salt of a basic compound wherein said mixture comprises one or morerotamers of said salt in a higher molar percent than their correspondingrotamers of said salt, said process comprising reacting said basiccompound with an acid in admixture with a solvent.
 2. The process ofclaim 1, wherein said molar percent is about 55:45 of said one or morerotamers of the salt to said other corresponding rotamers of the salt.3. The process of claim 2, wherein said molar percent is about 75:25 ofsaid one or more rotamers of the salt to said other correspondingrotamers of the salt.
 4. The process of claim 3, wherein said molarpercent is at least about 90:10 of said one or more rotamers of the saltto said other corresponding rotamers of the salt.
 5. The process ofclaim 1, wherein said basic compound is a pharmaceutical compound. 6.The process of claim 1, wherein said acid is a pharmaceutically usefulacid.
 7. The process of claim 1, wherein said acid is used in a molarratio of about 5:1 with respect to said basic compound.
 8. The processof claim 1, wherein said solvent is used in a molar ratio of about 20:1with respect to said basic compound.
 9. The process of claim 1, whereinsaid compound has the structure of Formula I:


10. The process of claim 9, wherein said higher molar percent refers tothe ratio of the salt of rotamer 1 to the salt of rotamer 2 of saidcompound of Formula I.
 11. The process of claim 9, wherein said highermolar percent refers to the ratio of the salt of rotamer 2 to the saltof rotamer 1 of said compound of Formula I.
 12. The process of claim 9,wherein said salt is selected from the group consisting ofbenzenesulfonate, citrate, camphorsulfonate, maleate, fumarate,phosphorate, p-toluenesulfonate, (D)-camphorate, and hydrochloride. 13.The process of claim 12, wherein said salt is maleate.
 14. The processof claim 1, wherein said solvent is an alcohol, ester, ketone,hydrocarbon or mixtures thereof.
 15. The process of claim 14, whereinsaid alcohol is selected from the group consisting of ethyl alcohol,isopropyl alcohol and mixtures thereof.
 16. The process of claim 15,wherein said alcohol is isopropyl alcohol.
 17. The process of claim 14,wherein said hydrocarbon is selected from the group consisting oftoluene, hexane, heptane and mixtures thereof.
 18. The process of claim14, wherein said ester is selected from the group consisting of ethylacetate, isopropyl acetate and mixtures thereof.
 19. The process ofclaim 13, wherein said maleate is formed at a temperature range of aboutambient temperature to about 90° C.
 20. The process of claim 19, whereinsaid solvent is ethyl acetate.
 21. The process of claim 19, wherein saidsolvent is isopropyl acetate.
 22. The process of claim 19, wherein saidsolvent is isopropyl alcohol.
 23. The process of claim 19, wherein saidsolvent is a mixture of ethyl alcohol and toluene.
 24. The process ofclaim 19, wherein said solvent is a mixture of ethyl acetate andheptane.
 25. The process of claim 13, wherein said maleate is formed atabout the ambient temperature over about 21 hours.
 26. The process ofclaim 12, wherein said salt is a citrate.
 27. The process of claim 26,wherein said solvent is acetone and the reaction is performed at about50° C. for about 23 hours.
 28. A process for preparing a mixture ofrotamer 1 and rotamer 2 of the maleate salt of the compound of Formula Iwherein the molar percent of said rotamer 2 to the molar percent of saidrotamer 1 in said mixture is in at

least about a 55:45 ratio, said process comprising: (a) preparing afirst intimate mixture of said compound of Formula I in a solvent; (b)maintaining said first intimate mixture at about ambient temperature toabout 90° C.; (c) preparing a second intimate mixture of maleic acid inthe same solvent stated in step (a); (d) combining said first intimatemixture and said second intimate mixture to prepare a combined intimatemixture and maintaining the combined intimate mixture at about ambienttemperature to about 90° C. for about 1-24 hours to induce formation ofthe maleate salt; and (e) isolating the salt.
 29. The process of claim28, wherein said solvent is an alcohol, ketone, ester, hydrocarbon ormixtures thereof.
 30. The process of claim 29, wherein said solvent isan alcohol.
 31. The process of claim 29, wherein said ester is isopropylacetate or ethyl acetate.
 32. The process of claim 28, wherein saidratio is about 75:25 for the molar percent of rotamer 2 to the molarpercent of rotamer
 1. 33. The process of claim 28, wherein said ratio isat least about 90:10 for the molar percent of rotamer 2 to the molarpercent of rotamer
 1. 34. A mixture of rotamers of a salt of a basiccompound wherein said mixture comprises one or more rotamers of the saltin a higher molar percent than their corresponding rotamers of the salt,said salt prepared by a process comprising reacting said basic compoundwith an acid in admixture with a solvent.
 35. The mixture of claim 34,wherein said solvent is a ketone, ether, hydrocarbon or mixturesthereof.
 36. The mixture of claim 34, wherein said basic compound is thecompound of Formula I:

said acid is maleic acid, said salt is maleate, and said molar percentis about 55:45 of rotamer 2 of the maleate salt to rotamer 1 of themaleate salt.
 37. An acid salt of a basic compound, wherein said basiccompound has the formula:

and wherein said acid salt is selected from the group consisting ofacetate, benzenesulfonate, benzoate, bicarbonate, bromide, calciumedetate, camphorsulfonate, carbonate, chloride/dihydrochloride, citrate,N,N-di(dehydroabietyl)ethylenediamine, edetate, 1,2-ethanedisulfonate,ethanesulfonate, fumarate, glucoheptonate, gluconate, glutamate,p-glycollamidophenylarsonate, hexylresorcinate, hyclate, hydrobromide,hydrochloride, 2-hydroxyethanesulfonate, hydroxynaphthoate, iodide,lactate, lactobionate, lauryl sulfonate, malate, maleate, mandelate,methanesulfonate, methylbromide, methylnitrate, methylsulfate, mucate,nafate, napsylate, nitrate, pamoate, pantothenate,phosphate/diphosphate, polygalacturonate, salicyclate, sodium succinate,stearate, subacetate, succinate, sulfate, tosylate, tannate,tartarate/bitartarate, 8-chlorotheophyllinate, triethiodide, adipate,alginate, aminosalicyclate, anhydromethylenecitrate, arecoline,asparate, bisulfate, butylbromide, camphorate, digluconate,dihydrobromide, disuccinate, glycerophosphate, hemisulfate,hydrofluoride, hydroiodide, methylenebis(salicyclate),naphthalenedisulfonate, oxalate, pectinate, persulfate,phenylethylbarbiturate, picrate, propionate, thiocyanate, undecanoate,acetylaminoacetate, N-acetyl-L-asparaginate, N-acetylcystinate,adamantoate, adipoate, N-alkylsulfamates, anthraquinone-1,5-disulfonate, arabolactansulfate, argininate, aspartate, betaine,carnitine, 4-chloro-m-toluenesulfonate, decanoate, diacetyl sulfate,dibenzylethylenediamine, dimethylamine, diguaiacylphosphate,dioctylsulfosuccinate, pamoate, fructose-1,6-diphosphate, glucosephosphate, L-glutaminate, hydroxynaphthoate, lauryl sulfate, lysine,2-naphthenesulfonate, octanonate, tannate and theobromine acetate.
 38. Afumarate salt of a basic compound, wherein said basic compound has theformula:


39. A citrate salt of a basic compound, wherein said basic compound hasthe formula:


40. A mono-benzene sulfonate salt of a basic compound, wherein saidbasic compound has the formula:


41. A maleate salt of a basic compound, wherein said basic compound hasthe formula:


42. A mono-tosylate salt of a basic compound, wherein said basiccompound has the formula:


43. A dihydrochloride salt of a basic compound, wherein said basiccompound has the formula: